The integrin alphavbeta3 is a receptor for the latency-associated peptides of transforming growth factors beta1 and beta3

Abstract

The integrins alpha(v)beta(1), alpha(v)beta(5), alpha(v)beta(6) and alpha(v)beta(8) have all recently been shown to interact with the RGD motif of the latency-associated peptide (LAPbeta(1)) of transforming growth factor beta(1) (TGFbeta(1)), with binding to alpha(v)beta(6) and alpha(v)beta(8) leading to TGFbeta(1) activation. Previously it has been suggested that the remaining alpha(v) integrin, alpha(v)beta(3,) does not interact with LAPbeta(1). However, here we show clearly that alpha(v)beta(3) does indeed interact with the LAPbeta(1) RGD motif. This interaction is similar to other alpha(v)beta(3) ligands in terms of the cations required for adhesion, the concentrations of LAPbeta(1) required for binding and the ability of a small-molecule inhibitor of alpha(v)beta(3), SB223245, to block the interaction. Using glutathione S-transferase fusion proteins we have mapped a minimal integrin-binding loop in LAPbeta(1) and then used this approach to probe the integrin-binding properties of the equivalent loops in LAPbeta(2) and LAPbeta(3). We show that the RGD motif of LAPbeta(3) also interacts with alpha(v)beta(3), in addition to alpha(v)beta(6), alpha(v)beta(1) and alpha(v)beta(5), whereas the corresponding loop in LAPbeta(2) does not interact with these integrins. These observations therefore correct a previously reported inaccuracy in the literature. Furthermore, they are important as they link alpha(v)beta(3) and TGFbeta, which may have implications in cancer and a number of inflammatory and fibrotic diseases where expression of both proteins has been documented.

Cross Talk among TGF- Signaling Pathways, Integrins, and the Extracellular Matrix

“…The TGF-b1 form of LAP (LAP1) binds the RGD-binding integrins avb1, avb3, avb5, avb6, avb8, and a8b1, and LAP3 binds avb6 and avb8 (but has not been tested with the other integrins) (Munger et al 1998;Annes et al 2002;Lu et al 2002;Mu et al 2002;Ludbrook et al 2003;Araya et al 2006). These RGD sequences are widely conserved among TGF-b genes in chordates, but are not found in other TGF-b superfamily members expressed by chordates, nor in nonchordates that express other TGF-b superfamily members.…”

Molecular Mechanisms of Glioma Cell Motility

“…In addition, integrin avβ3 and avβ5 expression is associated with disease progression. Both can bind to the latency-associated peptide (LAP) of the LAP-TGF-β complex and thereby release active TGF-β (81,82). In summary, integrins are substantial for glioma cell migration, establishing the link between the brain ECM and the tumor cells ( Figure 1).…”

Transforming growth factor beta (TGFB) signaling is activated during porcine implantation: proposed role for latency-associated peptide interactions with integrins at the conceptus–maternal interface

“…Like many ECM proteins, LAP1 and 3 monomers, corresponding to respective TGFB1 and 3 isoforms, contain an arginineglycine-aspartate (RGD) site. Previous studies have demonstrated that LAP binds to ITG heterodimers via this RGD sequence (Munger et al 1998, Mu et al 2002, Ludbrook et al 2003.…”